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In Interi erim res esults of Transpher er A, a multicen enter er, single-do dose, phas phase 1/2 clinic linical al tr trial ial of ABO-102 gene therapy y for Sanfilippo Syn yndrome Typ ype A (Mucopolysaccharidosis IIIA) Kevin M.

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SLIDE 1

In Interi erim res esults of Transpher er A, a multicen enter er, single-do dose, phas phase 1/2 clinic linical al tr trial ial of ABO-102 gene therapy y for Sanfilippo Syn yndrome Typ ype A (Mucopolysaccharidosis IIIA)

Kevin M. Flanigan Nationwide Children's Hospital, Columbus, OH, USA

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SLIDE 2

A group of four clinically indistinguishable lysosomal enzyme deficiencies that result in accumulation of the glycosaminoglycan (GAG) heparan sulfate (HS)

  • Global incidence varies by regions and it is estimated 0.17-2.35 per 100,000 births*
  • MPS IIIA is the most frequent subtype, caused by a deficiency in N-Sulfoglucosamine

Sulfohydrolase (SGSH)

Disease manifest as early as 12-24 months involving:

  • Central nervous system features predominate (gray > white matter)
  • Slowing and then regression of development, first speech/cognitive then gross motor
  • Impulsivity, hyperactivity, sleep disturbance, aggressive behavior, seizures
  • Relentless loss of skills progressing to dementia
  • Somatic features are milder than other MPS disorders
  • Coarse facial features/hirsutism, frequent otitis media, airway compromise, Umbilical

hernia, hepatosplenomegaly, mild dysostosis multiplex/short stature, heart valve thickening

No approved treatments available

  • 70% of children with MPS III do not reach age 18 years of age

Normal cell Cell with lysosome deficiency

Sa Sanfilippo Syn yndrome (MPS PS III)

2

* Zelei et al. 2018. Orphanet Journal of Rare Diseases

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SLIDE 3

Tr Transpher A: Phase 1/2 Clinical Tr Trial for MPS IIIA with scAAV9.U1.hSGSH

Intravenous Dosing

  • Cohort 1: 5 x 1012 vg/kg (n=3)
  • Cohort 2: 1 x 1013 vg/kg (n=3)
  • Cohort 3: 3 x 1013 vg/kg (n= 9 to 16)

Inclusion Criteria

  • 6 mo - 2 yrs of age or older than 2 years with a Developmental Quotient (DQ) ≥ 60 (using the Bayley Scale)
  • Confirmed Diagnosis of MPS IIIA by genetic and enzymatic determinations

Secondary Endpoints

  • Change from baseline in biomarkers after treatment
  • Change from baseline in Liver, spleen and brain volume by MRI
  • Neurocognitive function as measured by Mullen Scales of Early Learning or Bayley Scales of Infant and Toddler Development
  • Adaptive functioning, by Vineland Adaptive Behavior Scale (caregiver report)
  • Change from baseline in the Sanfilippo Behavior Rating Scale [ Time Frame: Month 6, 12, 18, 24 ]
  • Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) total score [ Time Frame: Month 6, 12, 18, 24 ]
  • Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) short form [Month 12, 24 ]

Primary Endpoint

  • Age Equivalent Developmental score compared with Natural History Study data
  • Product safety

3

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SLIDE 4

Screening (V1, V2) Día -45 to-1

Basal V3 V4 V6 V8 V7 V9 V10 V11 Final Visit V12

Day 0 (Treatment) Month 24 Month 12 Month 18 Day 180 Day 90

  • Lumbar puncture
  • MRI
  • Neurocognitive scales
  • Lumbar puncture
  • MRI
  • Neurocognitive scales
  • Neurocognitive scales
  • Auditive Assessment
  • Lumbar puncture
  • MRI
  • Neurocognitive scales

Cl Clinical T Trial D Design gn a and Sc Schedule o

  • f Vi

Visits

  • Lumbar puncture
  • MRI
  • Neurocognitive scales

4

Study Duration 24 months (followed by a Long-term follow up study for additional 3 years) Administration Single intravenous administration in 15-45 minutes. Hospital for 2 days. Steroids for the first 2 months (1 mg/kg prednisone or prednisolone) Comparator Group Natural History Studies Visit schedule Screening, basal, Days 7, 14, 30, 60, 90, 180, Months 12, 18 and 24

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SLIDE 5

24 patients have been screened:

  • 9 patients have failed screening
  • 14 patients have been treated (Cohort 1=3; Cohort 2=3; Cohort 3=8)
  • 1 patient in screening

Mean follow up as of January 2020

  • Cohort 1: 43 months
  • Cohort 2: 35 months
  • Cohort 3: 23 months

ABO-102 has been well tolerated

  • No infusion-related adverse events
  • No drug-related SAEs
  • Drug-related AEs have been Grade 1 or 2 and all resolved

⎼ Subclinical, transient ALT and AST elevations, without accompanying changes in GGT or bilirubin. ⎼ ELISpots have been negative with the exception of low and transient positive responses to AAV9 capsid peptides in 8 out of 14 patients ⎼ Mild and transient thrombocytopenia in 4 patients, not clinically significant (lowest level 69K)

Enr Enrollment t and nd Safety ty Upda pdate

5

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SLIDE 6

Ra Rapi pid, d, Dose-de depe pende ndent, t, and nd Sus ustaine ned d Reduc ducti tion n in n CSF Hepa paran n Su Sulfate Post Treatment

6

No Patients Screening Month 1 Month 6 Month 12 Month 24 Cohort 1 3 3 3 2 2 Cohort 2 3 3 3 3 3 Cohort 3 8 8 8 7 2

3 6 9 12 15 18 21 24 27

Post Injection Visits (Months)

50 100 150 200 250 300 350 400 450 500 550

Medain of CSF HS (nmol/L) ± (SE)

Cohort 3 Cohort 2 Cohort 1

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SLIDE 7

Re Reduction in Plasma Heparan Sulfa fate Levels

7

No Patients Screening Day 7 Day 14 Month 1 Month 2 Month 3 Month 6 Month 12 Month 18 Month 24 Cohort 1 3 3 3 3 3 3 3 3 3 3 Cohort 2 3 3 3 3 3 3 3 3 3 3 Cohort 3 6 5 5 8 8 8 8 7 5 2

3 6 9 12 15 18 21 24 27

Post Injection Visits (Months)

10 20 30 40 50 60 70

Medain of Plasma HS (pmol/mL) ± (SE)

Cohort 3 Cohort 2 Cohort 1

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SLIDE 8

Du Durable, e, Dos Dose-de depe pende ndent t Reduc ducti tion n in n Liver Volum ume Post t Treatm tment

8

No Patients Screening Month 1 Month 6 Month 12 Month 24 Cohort 1 3 3 3 3 3 Cohort 2 3 3 3 3 3 Cohort 3 7 8 8 8 2

1.00 1.25 1.50 1.75 2.00 2.25 2.50 3 6 9 12 15 18 21 24 27

Post Injection Visits (Months)

0.00 1 1 1 1 2

Mean of Normal Liver Volume ± (SE)

NHS Cohort 3 Cohort 2 Cohort 1

*Truxal et al, 2016, Mol Genet Metab *

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SLIDE 9

Na Natural-His Histor

  • ry Dis

Diseas ease e Prog

  • gres

ession ion Mod

  • del

el

DQ100 Truxal et al, Mol Genet Metab, 2016 Berman et al, J Inherit Metab Dis 2014 Shapiro et al, J Pediatrics, 2016 Wijburg et al, WORLD Symposium, 2018 9

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SLIDE 10

Na Natural-His Histor

  • ry Dis

Diseas ease e Prog

  • gres

ession ion Mod

  • del

el

The black solid line is the typical developmental pattern for children with MPS IIIA according to Natural History Data The gray shaded area is a 95% credible interval, incorporating variability from patient-to-patient differences and measurement error. The black dotted line shows the expected development for children without disease DQ100 10

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SLIDE 11

The black solid line is the typical developmental pattern for children with MPS IIIA according to Natural History Data The gray shaded area is a 95% credible interval, incorporating variability from patient-to-patient differences and measurement error. The black dotted line shows the expected development for children without disease DQ100

Mu Mullen’s Cogniti tive Age Equivalent t Post t Treatm tment t vs. Natu tural-His Histor

  • ry

Di Disea ease e Prog

  • gres

ession

  • n Mod
  • del

el

11

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SLIDE 12

Su Summary: y: Phase 1/2 St Study y Data (N= N=14) wi with ABO-102 102 (scAA AAV9. 9.U1.h U1.hSGSH)

Well-tolerated with no treatment-related SAEs and no clinically significant AEs 15-45 months post-dosing

  • Follow-up: Cohort 1 (n=3; 41.5-45 months), Cohort 2 (n=3; 33.5-36 months), Cohort 3 (n=8; 15-30 months)

Evidence of clinical benefit

  • Preservation of neurocognitive development in the three young patients treated before 30 months of age in

cohort 3 (18-24 months of follow-up)

  • Rapid and sustained, dose-related reduction in disease-specific biomarkers

⎯ CSF levels of heparan sulfate reduced to lower limit of quantitation ⎯ HS levels in the CSF provide evidence of CNS enzyme activity following ABO-102 administration (HS does not cross the blood-brain barrier)

  • Sustained decrease in liver volume, with up to 24 months of follow-up in Cohorts 1, 2 and 3

12

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SLIDE 13

Ac Ackno nowledgm dgments ts

  • Kevin Flanigan, MD
  • Kristen Truxal, MD
  • Kim McBride, MD
  • Kelly McNally, PhD
  • Krista Cope
  • Tabatha Simmons PhD

We thank all the patients and families and the MPS community for their participation in and support of this study

  • Nick Smith, MD, PhD
  • Mark Pertini, MD
  • Louise Jaensch, CRN
  • Maria Fuller, PhD
  • Maria Luz Couce, MD
  • Maria Jose de Castro, MD
  • Maria Teresa Oreiros
  • Sofia Gouveia
  • Luisa López Vázquez
  • María Tajes Alonso

Study Sponsor: Abeona Therapeutics

13

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SLIDE 14

Safety, tolerability y and preliminary y evidence of biopotency y in Transpher B, a multicenter, single-do dose, phas phase 1/2 clinic linical al tr trial ial of ABO-101 gene therapy y for Sanfilippo Syn yndrome Typ ype B (Mucopolysaccharidosis IIIB)

Kim L. McBride Nationwide Children's Hospital, Columbus, OH, USA

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SLIDE 15

Normal cell Cell with lysosome deficiency

Sa Sanfilippo Syn yndrome (MPS PS III)

2

A group of four clinically indistinguishable lysosomal enzyme deficiencies that result in accumulation of the glycosaminoglycan (GAG) heparan sulfate (HS)

  • Global incidence varies by regions and it is estimated 0.17-2.35 per 100,000 births*
  • MPS IIIB is the second subtype in frequency and it is caused by a deficiency in N-

Acetyl-Alpha-Glucosaminidase (NAGLU)

Disease manifest as early as 12-24 months involving:

  • Central nervous system features predominate (gray > white matter)
  • Slowing and then regression of development, first speech/cognitive then gross motor
  • Impulsivity, hyperactivity, sleep disturbance, aggressive behavior, seizures
  • Relentless loss of skills progressing to dementia
  • Somatic features are milder than other MPS disorders
  • Coarse facial features/hirsutism, frequent otitis media, airway compromise, Umbilical

hernia, hepatosplenomegaly, mild dysostosis multiplex/short stature, heart valve thickening

No approved treatments available

  • 70% of children with MPS III do not reach age 18 years of age

* Zelei et al. 2018. Orphanet Journal of Rare Diseases

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SLIDE 16

Tr Transpher B phase 1/2 Clinical Tr Trial for MPS IIIB with rAAV9.CMV.hNAGLU

Intravenous Dosing

  • Cohort 1: 1 x 1013 vg/kg (n=2)
  • Cohort 2: 5 x 1013 vg/kg (n=5)
  • Cohort 3: 1 x 1014 vg/kg (n= up to 5)

Inclusion Criteria

  • 6 mo - 2 yrs of age or older than 2 years with a Developmental Quotient (DQ) ≥ 60 (using the Bayley Scale)
  • Confirmed Diagnosis of MPS IIIB by genetic and enzymatic determinations

Secondary Endpoints

  • Change from baseline in biomarkers after treatment
  • Change from baseline in Liver, spleen and brain volume by MRI
  • Neurocognitive function as measured by Mullen Scales of Early Learning or Bayley Scales of Infant and Toddler Development
  • Adaptive functioning, by Vineland Adaptive Behavior Scale (caregiver report)
  • Change from baseline in the Sanfilippo Behavior Rating Scale [ Time Frame: Month 6, 12, 18, 24 ]
  • Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) total score [ Time Frame: Month 6, 12, 18, 24 ]
  • Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) short form [ Time Frame: Month

12, 24 ] Primary Endpoint

  • Age Equivalent Developmental score compared with Natural History Study data
  • Product safety

3

slide-17
SLIDE 17

Cl Clinical T Trial D Design gn a and Sc Schedule o

  • f Vi

Visits

Study Duration 24 months (followed by a Long-term follow up study for additional 3 years) Administration Single intravenous administration in 15-45 minutes. Hospital for 2 days. Steroids for the first 2 months (1 mg/kg prednisone or prednisolone) Comparator Group Natural History Studies Visit schedule Screening, basal, Days 7, 14, 30, 60, 90, 180, Months 12, 18 and 24

Screening (V1, V2) Día -45 to-1

Basal V3 V4 V6 V8 V7 V9 V10 V11 Final Visit V12

Day 0 (Treatment) Month 24 Month 12 Month 18 Day 180 Day 90

  • Lumbar puncture
  • MRI
  • Neurocognitive scales
  • Lumbar puncture
  • MRI
  • Neurocognitive scales
  • Neurocognitive scales
  • Auditive Assessment
  • Lumbar puncture
  • MRI
  • Neurocognitive scales
  • Lumbar puncture
  • MRI
  • Neurocognitive scales

4

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SLIDE 18

11 patients have been screened:

  • 3 patients have failed screening
  • 8 patients have been treated (Cohort 1=2; Cohort 2=5; Cohort 3=1)

Two pairs of siblings have been enrolled and treated

  • A 5.3 year old girl in Cohort 1 and her 4 months old sister in Cohort 2 (under a protocol waiver)
  • A 3.7 year old male and his 1.75 year old sister in Cohort 2

Enr Enrollment

5

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SLIDE 19

Mean follow up as of January 2020

  • Cohort 1: 19 months
  • Cohort 2: 6 months
  • Cohort 3: 0.5 months

ABO-101 has been well tolerated

  • No infusion-related adverse events
  • No drug-related SAEs
  • Drug-related AEs include
  • Subclinical, transient ALT and AST elevations, without accompanying changes in GGT or bilirubin
  • Mild and transient decrease in WBC and absolute lymphocyte counts in 2 subjects
  • AEs: grade 1/2 vomiting (n=5 subjects), anorexia n=2 subjects (associated with fever n=1), asthenia and vomiting (n=1)
  • ELISpot to AAV9 capsid peptide pools have been negative in all subjects, except in one subject in Cohort 1 that was positive

at Month 12 but negative again at Month 18

Sa Safety y Update

6

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SLIDE 20

Imp Improvemen ement in in Dis Diseas ease e Biomar iomarker ers in in CSF, Plas lasma, ma, Urin ine

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00

Chronological Age (Months) µmol/mmol creatinine

001-102 001-104 002-103

6 12 18 24 30 36 42 48 54 60 66 72 78 84

002-102 001-105 003-101

5 10 15 20 25 30 35 40 45 50 55 60 65 70

Chronological Age (Months) mg/mmol creatinine

001-102 001-104 002-103

6 12 18 24 30 36 42 48 54 60 66 72 78 84

002-102 001-105 003-101

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Chronological Age (Months) Plasma HS (pmol/mL)

Cohort 1 Cohort 2

6 12 18 24 30 36 42 48 54 60 66 72 78 84 Cohort 1 Cohort 2 Cohort 1 Cohort 2 Cohort 1 Cohort 2

Urine-GAGs Plasma-HS Urine-HS

7

Cohort 1 Cohort 2

CSF-HS

6 12 18 24 30 36 42 48 54 60 66 10 20 30 40 50 60 70 80 90 100 110 120

Crhonological Age (Months)

72 78 84

CSF HS (nmol/mL) Chronological Age (Months)

slide-21
SLIDE 21

1.0 1.5 2.0 2.5 3.0 6 12 18 24 30 36 42 48 54 60 66 72 .0 78 84

Cohort 1 Cohort 2 NHS

Multiples of normal liver volume Chronological Age (Months)

Re Reduction in Liver Volume Post Treatment

*

*Truxal et al, 2016, Mol Genet Metab; Whitley et al, 2018, J Pediatr

8

slide-22
SLIDE 22

6 1 2 1 8 2 4 3 4 2 4 8 5 4 6 6 6 7 2 7 8 8 4 9 9 6 1 2 1 8 1 1 4 1 2 1 2 6 6 12 18 24 30 36 42 48

Chronological Age (Months) Cognitive Age Equivalent 001-102 001-104 DQ100 DQ60 002-103 001-105 003-101

3 6

002-102 001-106

Cohort 1 Cohort 2

9

Mu Mullen’s Cogniti tive Age Equivalent t Post-Tr Treatment vs. Natural History

*Truxal et al, 2016, Mol Genet Metab; Whitley et al, 2018, J Pediatr NHS*

slide-23
SLIDE 23

Su Summary: y: Phase 1/2 St Study y Data (N= N=8) wi with ABO-101 101 (rAA AAV9. 9.CM CMV.h .hNAGLU) U)

Well-tolerated with no treatment-related SAEs and no clinically significant AEs or laboratory abnormalities

  • Follow-up: cohort 1 (n=2; 13 to 26 months); cohort 2 (n=5; 2.3 to 9 months); cohort 3 (n=1; 14

days) Clear biologic effect post treatment

  • Decreased CSF HS levels (maintained up to 12 months)
  • Reduction in plasma and urine HS and GAGs
  • Reduction in liver volume
  • Limited follow-up duration to date preclude adequate assessment of neurological outcomes

Began enrolling in cohort 3 (1E14 vg/kg)

10

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SLIDE 24

Ac Ackn knowledgments

  • Kevin Flanigan MD
  • Kristen Truxal MD
  • Kim McBride MD
  • Kelly McNally
  • Krista Cope
  • Tabatha Simmons PhD

We thank all the patients and families and the MPS community for their participation in and support of our studies

  • Bénédicte Héron, MD
  • Kim Giraudat
  • Claudia Ravelli, MD
  • Maire Christine Nougues, MD

11

  • Nick Smith, MD, PhD
  • Mark Pertini, MD
  • Louise Jaensch, CRN
  • Maria Fuller, PhD
  • Maria Luz Couce, MD
  • Maria Jose de Castro MD
  • Maria Teresa Oreiros
  • Sofia Gouveia
  • Luisa López Vázquez
  • María Tajes Alonso

Study Sponsor: Abeona Therapeutics